Many randomized clinical trials (RCTs) show acupuncture to be an effective treatment for diverse pain conditions. A closer look at this literature shows inconsistent findings: results tend to be confirmatory when RCTs compare acupuncture with 'no treatment' or 'standard care' controls; but inconclusive when RCTs compare genuine (verum) acupuncture with sham acupuncture suggesting that at least one healing component is mediated by something other than the acupuncture needles. A recent meta-analysis identified patient expectation of pain relief as the most robust predictor of acupuncture treatment efficacy, regardless of verum or sham group assignment. Neuroimaging studies have begun identifying testable mechanistic hypotheses for both acupuncture and placebo analgesia. Our recent studies on healthy subjects demonstrate that in the context of positive expectation, both verum and sham acupuncture significantly relieve pain, however each functions via separable and distinct brain mechanisms. The current proposal will test whether these distinct brain activity patterns associated with pain relief following verum and sham acupuncture can be replicated in patients suffering from chronic knee pain due to osteoarthritis (OA). We propose two experiments in patients with knee OA that directly build upon recent research in our laboratory. In the first experiment we will systematically boost patients' positive expectation for pain relief following verum or sham acupuncture, then quantify the relation between expectation, behavioral, and brain imaging (BOLD fMRI) measures of treatment response. In the second experiment, a 5-week longitudinal mechanistic treatment study of verum and sham acupuncture, fMRI BOLD responses to noxious stimuli obtained before and after the first and final treatment sessions will be examined with respect to individual expectation of treatment outcome to identify potential treatment response predictors. This significance of this innovative approach is that it could provide clear scientific evidence for how verum and sham acupuncture treatments modulate pain perception. The results of these experiments will advance our understanding of not only acupuncture and placebo analgesia mechanisms, but also help refine future research methods, and inform clinical practice. PUBLIC HEALTH RELEVANCE: The results of the proposed experiments will directly inform clinicians who treat patients with osteoarthritis of the knee about how to maximize the benefits of acupuncture treatments. And because the experiments specifically asks the question of what is the relation between a patient's expectation of how a treatment will relieve their pain and the outcome of the treatment, the results will potentially inform care givers about all treatments for osteoarthritis and other chronic pain disorders.